NZ223665A - Heterocyclic-substituted, labile keto derivatives of 3 substituted-1-alkylamino-2-propanols; medicaments and methods of treatment - Google Patents

Description

22 3 6 6 5 Priority Date(s): .. . . .3: ST?.

Complete Specification .Filed Class: j ^cQ / £? ■*+/ . £\ fc. /. .IS./. S3S.;...

Publication Date: i.6. WAR--fgjjf • • P.O. Journal, Mo: .. * NEW ZEALAND PATENTS ACT, 1953 v ' a v Date: A ' - //? ;« o/' COMPLETE SPECIFICATION \> °0 ./ V t LABILE KETONE DERIVATIVES of 3-SOBSTIT0TED-1-AKYLAMINO-2-PROPANOLS AND THEIR USE AS p-ADRENERGIC BLOCKERS tjj/we, university of florida, existing by virtue of the laws of the state of Florida, of 207 Tigert Hall, Gainesville, Florida 32611, United States of America hereby declare the invention for which 2> / we pray that a patent may be granted to i3*e/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page 1A) 223665 - 1a- LABILE KETONE DERIVATIVES OP 3-SUBSTITUTED-1-ALKYLAMINO-2-PROPANOLS AND THEIR USE AS g-ADRENERGIC BLOCKERS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel 3-substituted-1-alkylamino-2-propanol derivatives having B-adrenergic blocking properties; to pharmaceutical compositions containing same and methods of treatment involving their use.

Prior Art ^-adrenergic blockers were first reported to be useful for the therapeutic treatment of glaucoma in 1967 [Phillips et al, Brit. J. Ophthal., 1967 , 51 , 222] . In 1978 timolol was approved for market use and since that time the drug has become very popular with ophthalmologists as an effective antiglaucoma agent. Recently, however, a vast number of serious cardiovascular, respiratory, CNS, and ocular side effects secondary to topical ocular timolol administration has been reported [Ahmad, The Lancet, 1979, 2 , 1 028 ; Buskirk, Ophthalmology, 1980 , _87_, 447; Mishra et al, J_. Anaesth. , 1 983 , _55_, 897; and Linkewich et al, Am. J. Hosp. Pharm. , 1981, _38_, 699]. Currently, timolol is no longer the sole $-blocker used to treat glaucoma.

Befanolol, carteolol and metipranolol were introduced recently and a number of other newer 3-adrenergic antagonists (e.g., L-bunolol, betaxolol, celiprolol, cetamolol, etc.) are currently under investigation as antiglaucoma agents.

It became desirable to design an antiglaucoma drug which could be delivered to the eye compartments in a sustained and controlled manner with minimal systemic absorption and/or no systemic side effects.

NEW ZEALAND ^ PATENT OFFICE ••9 NOV 1990 f RECEIVED 223GG5 It was previously found that after topical application to the eye, esters of adrenalone but not ||j adrenalone itself can be converted via a reduction- hydrolysis sequence to deliver adrenaline (epinephrine) at the iris-ciliary body, the desired site of action [Bodor et al, Exp. Eve. Res.. 1984, 38, 621]. Research was conducted to ascertain whether lipophilic ketones could ^ also be reduced in the iris-ciliary body.

It was hypothesized that ketone precursors of 3-blockers which are also p-hydroxylamines like adrenaline could then possibly be converted to the active p-blockers in the iris-ciliary body by a reductive process. Various attempts, however, to synthesize the ketones 15 corresponding to a number of p-blockers (i.e., propranolol, timolol, carteolol, etc.) failed, due to the chemical instability of these p-amino-ketone esters.

It is an object of the present invention to provide novel hydrolytically sensitive precursors of the 20 ketone precursor of the p-adrenergic blocking p- hydroxylamines which are readily converted to the active p-blockers in the iris-ciliary body by combined hydrolytic and reductive processes.

SUMMARY OF THE INVENTION 25 This and other objects are realized by the present invention which provides novel compounds having the formula: Y Ar-X-CH2-C-CH2-NHR (I) or a pharmaceutical^ acceptable acid addition salt thereof, wherein -X- is -0-, -CH2 or -; =Y is a derivatized keto group which is hydrolyzable or 35 enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 20 4 x*0jah199tzl ..Oc ,0. ^ f V * o o'} p P tr d d o b o o carbon atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar is the 3-aromatic or heterocyclic residue of a l-alkylamino-2-5 propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having P-adrenergic blocking properties.

Another embodiment of the invention comprises a Ipj^ pharmaceutical composition in unit dosage form comprising a p-adrenergic blocking effective amount of one of the above described compounds or salts and a pharmaceutically acceptable carrier therefor.

A further embodiment of the invention comprises a method for eliciting a p-adrenergic blocking response 15 comprising administering a p-adrenergic blocking effective amount of one of the above described compounds or salts.

Another embodiment of the invention comprises an ophthalmic pharmaceutical composition comprising an effective intraocular pressure reducing amount of one of 20 the above described compounds or salts, or a corresponding compound or salt wherein =Y is =0, and a non-toxic ophthalmically acceptable carrier therefor. ; Yet another embodiment of the invention comprises a method for treating glaucoma or for lowering 25 intraocular pressure by administering to the eye or eyes an effective intraocular pressure reducing amount of a compound or salt of formula (I), or a corresponding compound or salt wherein =Y is =0. W' DETAILED DESCRIPTION OF THE INVENTION The present invention is predicated on the discovery that the hydrolytically sensitive oxime-type and other labile ketone groups of the compounds of the invention would enable the delivery to and hydrolysis and reduction of the derivative at the iris-ciliary site of / action to the active p-adrenergic blocking amino-alcohol. 223GG5 - 3a - The preferred compounds of the invention are those of the formula (I) above wherein Y is =N-OR1, .0—1 =N-NH2, =N-NR1R2 r • "^-"0— .s—I -R3' '0— -R-i or _ -R3 R]_ and R2 may be the same or different and are H, alkyl having from 1 to 8 carbon atoms or aryl or aralkyl having O10 from 6 to 15 carbon atoms; R3 is , -COOR^ or -C0N(R1)2; ' and Ar and R have the meanings set forth above.

It will be understood, however, that Y may be any group or substituent which is readily hydrolyzed or enzymatically converted to a hydroxyl group at the 15 intended site of action, preferably at the cornea or iris-ciliary body after administration of the parent compound to the animal undergoing treatment. (In addition, in the ophthalmic compositions and methods of the invention, =Y in the compounds of formula (I) and their salts can be =0, 20 i.e. the ketones corresponding to formula (I) can be utilized.) It is further preferred to employ those compounds of the above formula wherein R is a sterically hindered group such as the secondary or tertiary alkyls ^ 25 e.g., isopropyl, t-butyl, etc. Suitable aralkyl groups include benzyl, 3,4-dimethoxyphenethyl, 1-phenethylethyl, etc.; it being understood that by the term, "aralkyl", is intended any like hydrocarbyl group. o 223 fit; 5 Ar may be any aromatic or heterocyclic residue of the known 3-aromatic or 3-heterocyclic substituted l-alkylamino-2-propanol p-blockers, e.g., those residues having the formulae: 0' ^CO-CHj H3C COCHI HN-CON(C2H5)2 723665 o .ai2ai=ai2 hn-coch. o CH2CH2-0-CH3 :och, o HN-COC3H7 o -CH2CH=CH2 S N \=/ Cri2-C0NHz h3c / ch, ho. ho O new Zealand PATENT OFFICE "9 NOV 1990 RECEIVED ctc.

CONH- 011 r"" \ Any pharmaceutically acceptable acid may be used to form the acid-addition salts of the invention, e.g., HCl, F^SO/j, H3PO4, maleic, succinic, methanesulfonic, citric acids, etc.

The preferred compounds according to the present invention are those having the formulae in Table A. 22 3dG5 TABLE A Ar - X - CH2 - Z - CH2 - NH - R OH I CH N-OH II 2- = C Ar 0 0 0 0 C-blocker Name Compound No. No. 1 Propranolol J[a 2 Timolol l_b 3 Carteolol l£ 4 I-pr-Timolol Id, Alprenolol le G Atenolol 1£ 7 Befunolol l£ 8 Cetaxolol lh 9 Bevantolol l_i Bufuralol lj_ 11 Bunitrolol lk. 12 Bupranolol 13 Ceiiprolol c2h5 CN CI O CH- C0CH-, N1IC0H(C2H5)2 -CH(CH.)2 -ccm3)3 -C(CH3)3 -CHCCH3)2 -ffl(w3}2 -CHCCH3)2 -CH(CH-)2 •CH(CH-)2 ■CT2C>12 0-Cll3 -<°£- 0-CH3 2zj6b'j TABLE A (continued) Ar - X - CH2 - 2 - CH2 - NH - R OH I Z = CH N-OH Z = C Ar 0 S-blocker Name No. 14 Cetamolol IS FalinColol 1G 1CI-118,551 Compound No.

In lo i£ 0ch2c0nhch3 / CH., •<J -CCCH.). -cCCH5)3 -c(ch3)3 17 IPS-339 lr Ol—lOj -c(ch3)3 18 Labetolol Is 19 Levobunolol Mepindolol • lu 21 Metipr-anolol lv CONH- OH O °XH H ■ch3 h3c T ch3 ococh3 ch-I J -ch-ch2ch2 -c(ch3)3 -<2> -(ch(ch3)2 -ch(ch3)2 22 Metoprolol 1* 23 L-Moprolol 24 Nadolol ZS Diacet/1-nadolol 2G Cxprenolo] Is laa lbb cluck-o-ch, ^roc»3 HO ho -ch(ch3)2 -ch(ch3)2 TOsT CH3COTl3r CHnCOO'^-/^^ 0ch2-ch=ch2 NEW ZEALAND -c(ch3)3' PATENT OFFICE -9 NOV 1990 -C(CH3)^ RECEIVED o -ch(ch3)2 yi"r ■ 223665 TABLE A (continued) Ar - X - CH2 - B - CH2 - NH - R OH I Z = CH N-QH i> 2 = C Compound Ar (3-b locker• Name No. 27 Penbutolol No. lcc ■ -ccoy3 28 Pindolol 29' Pivaloyl Pindolol ldd lee olJ> I H co-CCCH3)3 -ch(ch5)2 -ch(ch5)2 o Toliprolol l6B CH. -ch(ch3).

Particularly preferred are compounds le, lh, 11, lcc, lk, lp, It, lv, lbb, li and Is. mew zealand patent office ~ 9 NOV 1990 deceived i 2.23665 The following overall reaction scheme may be employed to prepare the products of the invention: CH2-CH2-CH2CI Ar-OIl V fiOil I Ar-0CH2CCH2C1 RNH; !,'0H Ar-0CH2CCH2NHR > OH I Ar-0-CH2CH-CH2Cl DCC DMSO Py.TFA Nl/ WI20H*HCI <r Ar-0-CHPC-CH2Cl 6 HA IIOH II ArOCH2CCH2NHR. HA C A Ar-0-CH2CH-CH2 | NEW ZEALAND f PATENT OFFICE p f ! £9MVW0 J £ ^ iHSCEIVED 22 366 The conventional reaction of Ar-OH and epichlorohydrin with a small amount of morpholine as catalyst affords a mixture of the chlorohydrin 1 and the epoxide 2; the latter being converted to 1 by treatment with conc. HC1. Oxidation of 1 by the Pfitzner-Moffat method [Pfitzner et al, 1965 , J_. Am. Chem- Soc. , 87, 5661 and 5670] yields the ketone 3- Subsequent reaction of 3 with hydroxylamine ,HC1 gives the oxime 4, which is a mixture of the Z- and E-isomers. In the usual case the ratio is about 2:1, as determined by NMR [Silverstein, "Spectrometric identification of organic compounds", 1974, 3rd ed.: G. Clayton Bassler and Terence C. Morril, New York, Wiley].

The major product, 4 (E-), can be isolated by recrystall'ization from benzene. Treatment of 4 with isopropylamine in THF gives the oxime 5 essentially as the pure z-isomer, which can be converted to the HC1 salt 6. Alternately, the oxidation of the racemic B-blocker OH Ar-0-CH2-iH-CH2-NHR with DCC/(C0C1)2 at -20° to -78° 0 II will result in the ketone Ar-0-CH2"-C-CH2-NHR, which can be converted to 6 without isolation by adding H2N0H HCl.

The invention is illustrated by the following non-limiting examples wherein melting points were determined with a Fisher-Johns melting point apparatus and are uncorrected. The 90-MHz NMR spectra were taken on a Varian EM390 NMR spectrometer. TLC was performed on 0.25/mm Merck silica gel 60 F-254 glass plates. new ZEALAND _ patent OFRCE j £»9NOV1990 received 223 G o 5 EXAMPLE 1 The synthesis of the propanolone oxime (6a) is a typical example. 1-(I sopropylamino )-3-( 1 -naph thyl oxy )-2-propanone oxime HCl, Propranolone oxime hydrochloride (6a) 3-Chloro-1-(1-naphthyloxy)-2-propanol (la) A mixture of 1-naphthol (20g, 0.14 mole), ephichlorohydrin (51.3g, 0.55 mole), and morpholine (0.7 ml) v/as heated at 100-1 20°C for 7.5 h. Excess epichlorohydrin and morpholine were removed under reduced pressure, the residue was dissolved in chloroform and shaken with TO ml of conc. IICl to convert (2a) to the ch'lorohydrin (la). The organic layer was separated and washed with water, then with dil. NallC03 and finally with water. It was dried over anhydrous MgSOjj and concentrated to yield 29.8g (98%) o£ the crude product. This was used in the next step (oxidation) without purification.

Purification of a sample o£ the crude (la) was carried out by column chromatography (silica gel: Aldrich 100-200 mesh, 60 Ax4W, eluent CHCI3). NMR (CDCI3) 6 8.15 (m, 1H), 6 7.75 (in, 1H) <5 7.5-7.2 (m, 4H), 6 6.7 (d, d, J=7 Hz, J=1 Hz, 1H), 5 4.35-3.50 (m, 5H), 5 2.9 (d, J=6 Hz, 1H). 3-Chloro-l-(l-naphthyloxy)-2-propanone ( 3a) To a solution of 1 ,3-dicyclohexylcarbodiimide (DCC) (47.1g, 0.223 mole DMSO (36 ml), and pyridine (3.6 ml) in diethyl ether (300 ml) was added a solution of (1a) (18.Og, 76 mmole) in diethyl ether (36 ml). To this solution was then added c?ropwise a solution of trifluoroacetic acid (1.8 ml) in diethyl ether under ice-water cooling, and the mixture was stirred at room temperature for 1 h ana allowed to stand overnight solution of oxalic acid ( 18g) in MeOH was added to ? 2 3 6 6 5 reaction mixture in small portions, and the stirring was continued for 0.5 h. The dicyclohexylurea was filtered and washed with ether. The filtrate was washed with a 5% NatiCC>3 solution, then with water and dried over anhydrous MgSO^j . From the filtrate 6.3g of the desired compound was recovered. The mother liquor was concentrated under reduced pressure and the residue was recrystallized from 2-propanol to yield an additional 3.3g. The total yield was 9.6g (Y=56%). This product was used in the next step without further purification. A pure sample was obtained by column chromatography (silica gel: Aldrich 100-200 mesh, 60 A x 7W, eluent CHC13 : hexane = 3.1). NMR(CDCl3) 8 .25 (m, 1H) , 5 7 . 00 (m, 1H), 5 7 .65 7.20 (m, 411), 5 6.75 (d, J=7 Hz, IK), 6 4.83 (s, 2H), 6 4,43 (s, 2H). 3-Chloro-l-(1-naphthyloxy)-2-propanone oxime (4a) A mixture of (3a) (1.0g, 4.26 mmole), hydroxylamine hydrochloride (0.36g, 5.1 mmole), and DMSO (10 ml) was heated at 40-60°C for half an hour. Water (40 ml) was introduced and the solution was extracted with CHCI3. The organic layer was washed with water several times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude yield was 1.1g (Y=100%). Further purification was carried out by column chromatography (silica gel: Aldrich 100-200 mesh, 60 A x 30W, eluent: benzene:AcOEt=4 :1) . The product was a mixture of Z- and E- isomer (e:z=2:i). This isomer mixture could be used in the next step. NMR (CDCI3 + DMSO-d6 (1 drop) 6 10.85 (s, 0.33H, -NOH of z-isomer), 5 10.75 (s, 0.67H, -NOH of e-isomer), 6 8.4-0.1 (m, 1H), 6 7.9-7.65 (m, 1H) , 5 7.6-7.2 (m, 4H), 6 6.95-6 .7 (m, 1H), 6 5.2 (s, 1.33H, OCK2 of e-isomer), 5 4.9 (s, 0.67H, OCH2 of z-isomer), 6 4.45 (s, 0.67H, -CH2CI of z-isomer) 6 4.3 (s, 1.33H, -CH2Cl of E-isomer).

The e-isomer was isolated from the crude product by recrystal1ization from benzene. M.p. 162-153°C. 223665 1- (Isopropylamino)-3- (1-naphthyloxy)-2-propanone oxime, Propranolone oxime (5a) A mixture of (4a) (2.5g, 10 mmole), isopropylamine (6.0g, 8.7 ml, 100 mmole), and THF (50 ml) was heated at 50°C for 1.5 h. The reaction mixture was concentrated under reduced pressure. To the residue was added dil. NaHCC>3 and the solution was extracted with ethyl acetate. After the organic extract was shaken with dil. HCl solution, the separated aqueous layer was made basic with dil. HCl solution, extracted with AcOEt, dried over anhydrous MgSC>4, and concentrated under reduced pressure. The crude yield was 2.6g (Y=95%). The crude product was purified from a mixed solvent of isopropyl ether ana- hexane. The pure yield was 0.98g (Y=36%). * M.p. 131.5-132.5°C. This product was the z-isomer only. NHR(CDC13) 6 8.30-8.20 (m, 1H, one of H of naphthalene), <5 6.90-6.80 (m, 1H, one of H of naphthalene), <5 5.16 (2, 2'rl, -0CH2-), 5 3 .70 (s, 2H, -CH2N-), 6 3 .05-2.70 (m, 1H, N-CH<), 6 1.10. l-(Isopropylamino)-3-(1-naphthyloxy)-2-propanone ox ime hydrochloride, Propranolone oxime Hydrochloride (6a) To diethyl ether saturated with HCl gas was added a solution of propranolone oxime (5a) (0.30g) in diethyl ether. The mixture was stirred at room temperature for 0.5 h. The precipitated white crystals were filtered and dried in vacuo overnight. The yield was 0.32g (Y= 94%). This product was essentially pure z-isomer. NMR (DMSO-d6) 6 12.00 (s, 1H, -NOH), 5 8 .30-8 . 1 5 (m, HI, of naphthalene), 5 7.95-7.80 (m, 1H, of naphthalene), 6 7.65-7 .30 (m, 411, part of naphthalene), 5 7 .05-6 .95) (m, 1H, one of H of naphthalene), <S 5.15 (s, 213, -OCH2) < 6 3 .96 (s, 2H, -CH2N), 5 3 .55-3 .20 (m, 2H, NCH, -NK), 6 1.27 (d, J=6 Hz, 611, - (CH3 ) 2) .

Anal. (C16H2002N2-HC1) C,H,N. 223665 EXAMPLE 2 1 — ( tert-Butylamino)-3- [ ( 4-morpholino-l,2,5—fchiadiazol-3-yl)oxy]-2-propanone oxime oxalate (timolone oxime oxalate, (6b) 3-Chloro-l-[ (4- morphol ino- 1 ,2,5- thiadiazol-3-yl)oxy]-2-propanol, 5 (lb) was synthesized according to the method given for (la). Yield 83%; the crude compound was used in the next step. NMR (CDCI3) 5 4.5 (d, J=5 Hz, 2H), 5 4.2 (pentet, J = 5 Hz, 1H), 6 3.8- 6 3 .65 (m, 6H), 5 3 .55-3 .40 (m, 411). The peak of C-OH could not be identified. 3-Chloro-l-[ (4- morphol ino-1 ,2,5- thiadiazol-3-yl)oxy]-2- propanone (3b) was synthesized according to the method given for (3a). Yield: 65%. The crude product was used in the next step. Purification of the crude product (recrystallization from 2-propanol) yielded the pure 15 sample. NMR (CDCI3) 6 5.22 (s, 2H), 5 4.13 (s, 2H), 3.75 (m, 4H, 6 3.50 (m, 4H). 3-Chloro-l-[ (4-morphol ino- 1,2, 5-thiadiazol-3-yl )oxy]~ 2-propanone oxime (4b) In a 500 ml round-bottomed flask were placed 20 (3b) (13.6g, 49 mmole) and hydroxylamine hydrochloride (5.1g, 73.4 mmole), in an ethanol-DMF mixed solvent (266 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (2L) and was extracted with ether. The organic extract was washed 25 well with water, dried over anhydrous MgS04, and was concentrated in vacuo at 30°C. The crude yield was 11.8g (Y=83%). The product was a mixture of Z- and E- isomers (E: z= 1 . 1 : 1.0). This crude mixture can be used in the next step. NMR (CDCI3) 6 9 .30 (broad s, 0.5H, -NOH of 30 z-isomer), 5 9.10 (broad s, 0.5H -NOH of E-isomer), 6 5.35 (s, 1H, 0-CH2 of e-isomer) 6 5.10 (s, 1H, z-isomer), <5 4.30 (s, 1H, -CH2-N of z-isomer), 5 4.17 (s, 1H, -CK2-N of E-isomer), 6 4.8-4.7 (m, 4H) 6 (m, 4H). / patent office ?9 NOV1990 22366 5 1 -( tert-Dutylamino) -3-[ (4-morpholino-l,2,5 - thiadiazol-3-yl) oxy ] -2-propanone oxime, timolone oxime (5b) In a 250 ml round-bottomed flask fitted with a dropping funnel was placed (4b) (9.8g, 33.5 mmol) in TIIF (147 ml). The solution was cooled in an ice bath, and a solution of tert-butylamine (12.2g , 168 mmol) in THF (20 ml) was added through the dropping funnel during 10 minutes keeping the reaction temperature at -5 to 0°c (pH 6-7). The stirring was continued for 1 hour at the same temperature. The solvent was evaporated under reduced pressure at 25°C. To the residue was added diluted HCl (2.8 ml conc. HCl) and it was extracted with ethyl acetate. To the aqueous layer separated was added a dil. NaHC03 solution (NaHC03 3.1g) at .-5°C (pH -v 6-7). It was extracted with ether to remove some impurities. Small amounts of NaIiCC>3 (0.1-0.3g) were added to the aqueous layer to make it slightly basic, and the mixture was extracted with ether. This procedure was repeated 4 times (pH was about 8) and another 3 times after raising the pEI to about 9 with dil. NaOH solution. The organic extracts were combined, washed with water, dried over anhydrous MgSO^j, and concentrated in vacuo. Yield 3.1g (Y=28%). The crude product was triturated with isopropyl ether to yield 2.8g. This was recrystallized from isopropyl ether to yield 1.8g (Y=16%) of pure compound. 1 - ( tert-Butylamino)-3-[( 4-morpholino-l, 2 , 5-thiaaiazol-3-yl )oxy]-2-propanone oxime oxalate, timolone oxime oxalate (6b) In a 50 ml round bottomed flask was placed a solution of oxalic acid (0.2 Og, 2.22 mmole) in ether (10 ml). To this solution was added a solution of (5b) (0.43c, 1.3 mmole) in ether. The mixture was stirred at room temperature for 1 hour. The white non-hygroscopic crystals were filtered and dried in vacuo. Yield 0.53g (Y=971).

M.p. 1 65-1 66° (dec:). NMR (CDCL3) 6 5.3 (s, 2H),/ NEW ZEALAND patent OFFfCE "'NOV 1990 3 m o 223 6 V) 5 6 3.9-3.7 (m, 4H), 6 3.6-3.4 (m, 60), 6 1.1 (s, 9 EJ) .

Anal. (C-j 8^25®7^5 ) / C,H,N.

EXAMPLE 3 5— [ 3 — (tert-Butylamino)-2-(hydroxylimino)propoxy]-3,4-dihydrocarbo-styril hydrochloride, carteolone oxime HCl (6c) - ( 3-Chloro— 2-hydroxy propoxy)-3,4-dihydrocarbostyril (lc) In a 250 ml round-bottomed flask fitted with a reflux condenser were placed 5-hydroxycarbostyril (15.0g, 10 92 mmole), epichlorohydrin (34.2g, 0.37 mole), morpholine (1.5 ml), and dioxane (90 ml). The mixture was refluxed for 16 hours, then it was concentrated in vacuo (20 mm/Hg) at 80-90°C. To the residue was added 300 ml of 2N HCl, stirred for 15 minutes, then 0.8-1.0 L of ethyl acetate was 15 added and the mixture was stirred vigorously for 0.5 hour. The organic layer was separated, washed well with water, then with dil. NaHCC>3 and was concentrated in vacuo.

Yield: 19.9g (85%).

NMR (DMSO-do) 6 10.3 (s, 1H -NH-), 6 7.25-6.50 (m, 3H, Ph), 20 6 4.20-3.60 (m, 5H, OCH2CHCH2Cl), 6 3.00-2.30 (m, 4H, -CH2CH2CO-) . - ( 3-Chloro—2- oxo)propoxy)-3,4-dihydrocarbostyril (3c) was synthesized according to the method described for (3a). NMR (DMS0-d6) <5 10.10 (s, 1H, -NH-) , 6 7 .20-7.00 (m, 1H, Ph) , 25 6 6.65-6.50 (m, 2H, Ph), <5 4.95 (s, 2H, OCH2), 6 4.70 (s, 2H, CH2Cl), 6 3.0-2.8 (m, 2H, -C-CH2C0-), 6 2.5-2.3 (m, 2H, -CH2-C-C0-). -[3 —Chloro—2— (hydroxyimino)propoxy]-3,4- dihydrocarbo-styril (4c) was synthesized similarly to the method given 30 for (4b). NMR (DMSO-d6) 5 11.88 (s, 0.3H), z- of NOH), 11.80 (s, 0.7H, e- of NOH) 6 10.08 (s, 1H, -NH-), 6 7.30-6.50 (m, 3H, Ph), 6 4.93 (s, 1.4H, E- of OCH2) 6 4.73 (s, 0.6H, z- of OCH2 ) , 6 4 .38 (s, 2H, Z & E- of CH2C1), 6 3 .00- 6 2.80 (m, 213, C-CH^O^f/* 6 2.65-2.40 (m, 2H, CH2-C-CO). u ^0janf9q*c>\ 223665 -[3-(tert-Butylamino)-2-(hydroxylimino)propoxy]-3,4- dihydrocarbostyril, carteolone oxime (5c) In a 100 ml round-bottomed flask fitted with a dropping funnel were placed (4c) (2.0g, 7.45 mmole) and T1IF S (70 ml). The solution was cooled to 0°C and a solution of tert-butylamine (0.82g, 1.17 ml, 11.2 mmole) in THF was introduced through the dropping funnel. The mixture was stirred under cooling for 2 hours. To the reactive mixture was added a solution of oxalic acid (1.40g, 16.4 mmole) In 10 THF. The precipitate was filtered, triturated with water (600-700 ml) by stirring well for 15 minutes, and it was filtered again. The filtrate was extracted with ethyl acetate several times. The aqueous layer was cooled to 0°C, basified with a dil. NaIlCC>3 solution (NaHC03 15 0.81g), and was immediately extracted with ethyl acetate." The extract was evaporated in vacuo (20 mHg) at 30°C.

Yield: 0.63g (28%). Recrystallized from i-propanol, the product was z-isomer. M.p. 177-180'C (dec.) NMR (DMSO-dg) 6 11.0PPM(s, 1H), 6 10.1 (s, 1H), 6 7.3-7.1 20 (m, 1H), 6 6.7-6.5 (m, 2H), 6 4.9 (s, 2H), 6 3.3 (s, 3H contain NH), 6 3.0—2.8 (m, 211), 6 2.6-2.3 (rn, 211), 6 1.05 (s, 9H). -[3-(tert-Butylamino)-2-(hydroxylimino)propoxy]-3,4-dihydro-, carbos tyril Hydrochloride, carteolone oxime hydrochloride o r* (6c) The free base (5c) was converted to the hydrochloride salt (6c) in ether with HCl gas. M.p. 1 67-1 69 °C (dec.). I new^ealand' Anal. (C16H24O3N3CI) C,H,N. U FAT£NT °FF'CE II B9NOVJ990 EXAMPLE 4 RECEIVED l-(Isopropylamino)-3-[(4-morpholino-l ,2,5-thiadiazol-3-yl)oxy]-2-propanone oxime hydrochloride (6d): 1 (Isopropylamino )-3-[ (4-morpholino-l,2,5-thiadiazol-3-yl)oxy]- 2-propanone oxime (5d ) In a 200 ml round-bottomed flask were placed 3-chloro-1-[3-(4-mor?holino-1,2,5-thiadiazyloxy)]-2- f&sm'----- 223665 propanone oxime (4b) (3.53g, 12.1 mmole), isopropylamine (3.56g, 60.3 mmole), and THF (71 ml). The mixture was stirred at room temperture for 2.5 hours. The reaction mixture was concentrated in vacuo at room temperature. The residue was triturated with isopropyl ether and precipitated crystals were filtered with suction. The crystals were dissolved in dil. HCl solution. To the solution was added ether and NaHC03 in small portions under vigorous stirring conditions. The organic layer was washed with water and dried over anhydrous MgSC>4, and concentrated in vacuo. Yield: 0.42g (Y=11.6%) from isopropyl ether. l-(lsopropylamino )-3-[ (4-morpholino-l, 2,5-thiadiazol-3-yl) oxy] -2-propanone oxime Hydrochloride (6d) The oxime (4b) (0.25g) was dissolved in ether and ether saturated with HCl was introduced dropwise into the solution. The mixture was stirred for 10 minutes, filtered and dried in vacuo overnight. Yield: 89%.

Anal. (C-, 2H22N5O3S CI) C,H,N.

Elemental Analyses 1 - l-(Isopropylamino)-3-(l-naphthyloxy )-2-propanone oxime hydrochloride, propranolone oxime hydrochloride (6a), C1 6H21°2N2C1.

Calc.: C, 62.23; H, 6.85; N, 9.07 Found: C, 62.32; H, 6.89; N, 9.05. 2 - 1-( tert-Butylamino)-3-[(4-morpholino-l,2,5-thiadiazol-3-yl)oxy]- 2-propanone oxime oxalate, timolone oxime oxalate (6b) , C15H25O7N5S C13II23O3N5S (cooh) 2.

Calc.: C, 42.95; H, 6.01; N, 16.70 Found: C, 4 3 .00; II, 6.04; N, 16.67 new ZEALAND patent OFFICE E 9 NOV 1990 I " received 223665 O 3 — 5— [3~ (tert-Butylamino)-2-(hydroxyimino)propoxy]-3,4~ dihydrocarbostyril hydrochloride, carteolone oxime hci (6c), C-j 5H24O3N3CI.

Calc.: ' C, 56 .22; H, 7.08; N, 12.30 Found: C, 5 6.10; H, 7.13; N, 12.21 4 - 1- (Isopropyl amino) -3- [ (4-morpholino-l, 2,5-thiadiazol-3-yl) oxy ]- 2-propanone oxime hydrochloride (6d), C12H22N5°3S cl- 1/3 H2°- Calc.: C, 40.27; H, 6.30; N, 19.57 Found: C, 40.54; H, 6.42; N, 19.46 The following non-limiting examples illustrate the pharmacological properties of the compounds of the invention.

EXAMPLE 5 o 50 new zealand £ patent office f r9NOVtifoO Effect on the Intraocular Pressure (IOP) of Rabbits: Adult male New Zealand albino rabbits weighing 2.5 - 3.5 kg were used. The animals were kept in individual cages with free access to food and water. Intraocular pressure was measured using a Digilab model 30R pneumatonometer. The pneumatonometer readings were checked at least twice a day using the Digilab calibration verifier. All measurements were obtained from unrestrained, unanesthetized rabbits. One drop of 0.5% propacaine (Ophthetic-Allergan Pharmaceuticals, Inc.) diluted 1:2 with saline was instilled in each eye immediately prior to IOP measurement. Drugs were administered as 1 or 2.5% solution in buffer pH 7.4 or in saline in both eyes of a group of at least four rabbits. Another group of at least three rabbits served as control and was administered the carrier only. IOP was recorded ■©fter 30 and 60 minutes and then after 2, 3, 4, 6 and 8 lours following the drug or carrier adminis tra tion. Values re given as means t standard error (S.E.) of the mean. received 01 223665 The significance of the change was determined using the student's t-test.

The animals were also observed for local action of the drugs on the eyes, e.g., irritation, congestion, 5 redness, lacrimation, etc.

The results are set forth in Tables 1-3. o o p^b^tALANd 0at£a/t office * 9 nov $90 REC£jV£d 33 rn O m < rn o •1 1 c 'Si m < H N o? *TJ £ Igflffect C Table 1 . .. of I i solutions of pTopranolol*HC1 (la) and propranolone oxime'HCl (6a ) on the.'IOP (mm/fig) of rabbits.

Time after, admlni stratlon Propranolol hci (la) 1/ Propranolone oxime hci (ga ) (l'X) Control . Treated % change ' after t reatment Control Treated % change after t reatment N H Zero 28.8 i 0.33 • 30.8 i 0.40 0.00 29.3 •L 0.50 27 .8 i 0.62 0,00 m i n . 32.0 • i 0.44 28.0 X 0.56 -9.10* • 28.2 X 0.65 26.9 1 0.58 -3.23 GO mi n, 32.7 i 0.26 27.6 ± 0.62' -10.39* 29 .1 4* 0.60 ' 24.0 + 0.60 -11.51* 2 hrs , 31.3 + 0.31 29.1 0.38 - 5.52 27.7 0.57 23.4 i .•0.51 -15.02** 3 hrs . .8 X 0.32 •27 .4 dr 0.54 -11.04* 26.3 ± 0.40 23,3 i 0.35 -16.18** 4 hrs . 29.9 i 0.61 2 8\ 2 i 0.<18 -8.44* 26.8 + 0.33 22.2 i 0.42 .-20,14** 6 hrs , .8 ± 0.38 29.0 ± 0.45 -5 .84 28.8 ± 0.52 ' 25.8 *X X 0.56 -7.08* 0 hrs, "* yJO.7 X 0.26 .2 ± 0.43 -1.95 29,2 X 0.51 27.9 X 0.62 + 0.50 * Significant decrease 1n 1.0.P, (P<0.05) **Hlghly significant decrease 1n 1.0.P, (P<0.01) rv> 1>J On On un 33 m o m < O !!Z 2N ^ rrt m o < < 0> m o S§ f Table 2 Effect of 2.5% solutions of propranolol•HCl (la) and propranolone oxime HCl ( 6a ) on the IOP (mm/Hg) of rabbits.

Propranolol • HCl (la) (2.5i) Propranolone oxime'HCl (6a ) (2.55) % change ' change Time after after after Administration Cont rol Treated treatment Control Treatment treatment Zero 26.6+0.56 .4 + 0 .56 0.00 • 25.8+0.55 26 .0+0.48 0.00 mi n. 28.0+0.93 27.6i0.56 +8.66* 27.2+0.82 26 .5 + 0.63 + 1.92 6 0 mi n . 26.6+0.51 27.9+0.60 +9.84* 26.2+0.63 23 .4 + 0.55 -10.00* 2 hrs . 24.6 + 0.19 .7+0.55 +1.18' 26.3+0.71 22.6i0.43 -13.08* 3 hrs. .6±0 . 31 .7i0.39 + 1.18 26.7i0.66 21.2+0.28 -18.46* 4 hrs. .2+0.64 .6i0.46 + 0.79 26.8i0.34 .4i0.34 -21.54** 6 hrs . 26.4+0.35 .4i0 .54 0.00 .9+0 .54 23 .6i0.48 -9.23* 8 hrs. 26,0±0,5 2 .2i0.68 -0.79 26.0i0.47 - ■ " — - . 25.8 + 0.65 -0.77 ^Significant change (P<0.05) **Hlghly significant change (P<0.01) to to ■x> rv> CN ON ai ov> ' Table 3 -§ £ c3 ■' / - Effect of 1< of solutions of timolol maleate (lb) and timolone oxime oxalate (6b ) on the IOP (rrro/Hg) of rabbits Timolol maVeate (lb) 1< Timolone oxime oxlate (6b) IX ^Change X change Time after ' after after administration Control Drug-treated treatment Control Drug-treated treatment 0 .7210.5<i 29.19i0.78 0,00 28.72i0.54 28.44+.63 0.00 min. 26.62+0.59 26.00+1.23 -10.93* 26.62+0.59 27.75+0.68 -2,43 1 hr. 28.10+0.85 27.25+1.12 6,65 28.10+0.85 24.30+0.63 -14.56** 2 hr. 27.02i0.92 27.21i0.58 6.78 27 .02±0.92 24 .00i0.44 -15.61** 3 hr. .95+0.4-1 .00+0.87 14.35** .95+0.44 .13+0.96 -'11.64** 4 hr. 26,45+0.57 24.88+1.00 14.77** 26,45+0.57 26.93+0.48 -5.31 hr. 27.09i0.55 24.25+1.18 16.92** 27.09+0.55 26.88i0.52 -5.49 6 hr. 27.88+0.56 .58+0.85 12.37** 27 .88±0.56 28.78iO.91 +1.20 0 hr. 27.67+0.63 26.33+0.40 9.80* 27.67+0.63 26.33+0.40 -7,42 'Uiynilicant. chmiyu (l'<u.0b) **liighly significant change (p<0.01). 223665 o These results reveal that the ketoxiine analogs of both propranolol and timolol display a certain degree o£ ocular hypotensive activity. Propranolone ketoxime (6a) has shown the highest activity at both tested concentration 5 levels, 1 and 2.5%. This activity was much more pronounced and prolonged than that of propranolol itself administered at the same dose levels (Tables 1 and 2). In addition, the ketoxime (6a) was completely devoid of the ocular irritation which always accompanied propranolol 10 administration at both dose levels. This irritant activity might have contributed to the reduced action of propranolol on the IOP at the 1% dose level and, also, might have completely masked its ocular hypotensive activity at the 2.5% dose level. Timolone ketoxime (6b) has also shown a 15 significant ocular hypotensive activity which was faster in its onset and shorter in its duration than timolol (lb) v itself (Table 3). On the other hand, the other ketoxime precursors, the ones for the N-isopropyl analog (6d) of (6b) and (6c) for carteolol, showed low activity at the 20 dose levels used but showed some B-antagonist activity.

EXAMPLE 6 Effect on resting heart rate and on isoprenaline- induced tachycardia in rats: Male Sprague-Dawley rats weighing 150-250 g were used. Each animal was anesthetized with sodium pentobarbital (50 mg/kg) and the jugular vein was cannulated with PS50 tubing. This cannula was 50 subcutaneously threaded around the neck and exteriorized dorsally. The cannula was filled with heparin solution (1000/yl) and sealed with a solid 22-gauge stylet. Animals were housed in individual stainless steel cages and at least 24 hours were allowed for recovery from the surgery. 55 Food and water were provided ad libitum. On the day of patent office F9NOV/990 Received the experiment, the heart rate of each rat was monitored with a plethsmograph and the data recorded on a Physioscribe II recorder. One hour was allowed as an equilibration period before any drugs were administered. 5 Drugs were dissolved in normal saline as 0.3% solution and were administered intravenously at a dose of 6 mg/kg. The resting heart rate was then recorded after 1, 3, 5, 10 and 15 minutes following i.v. injection. Isoprenaline (Isoproterenol bitartarate), was then administered 0 subcutaneously at a dose of 50 yg/kg and the heart rate was recorded for 3, 5, 10, 15, 20, 30, 45 and 60 minutes after administration. A control group of seven animals was intravenously administered saline solution and was treated exactly in the same manner as the drug-treated groups. 5 The significance of the difference between the effect of saline solution and the drugs under investigation on the resting heart rate and on isoprenaline tachycardia was analyzed using the student's "t" test. Values are given as mean ± S.E. of the mean. The results are depicted 0 in Figure 1 which depicts the mean change in heart rate over time for ( □ ) propranolol HCl (la), ( A ) timolol maleate (lb), ( 0 ) carteolol HCl (1c), ( q ) propranolone ketoxime HCl (6a), ( V ) timolone ketoxime oxalate (6b), ( A ) N-isopropyl timolone ketoxime HCl (6d), ( El ) 5 carteolone oxime HCl (6c) and (- - -) saline solution.

In another set of experiments the effect of the oral administration of propranolol Hci (la) and propranolone oxime HC1 (6a) in doses of 25, 50 and 100 mg/kg on the resting heart rate and isoprenaline-tachycardia was evaluated in rats. Drugs were administered to groups of 5 rats using a stomach tube and the heart rate was recorded for 1 hour. Then isoprenaline (50 yg/kg, s.c.) was administered and the heart rate was recorded after 3, 5, 10, 15, 20, 30, 45 and 60 minutes following administration. A control group of 5 rats was treated exactly in the same manner after the oral administration of the appropriate volume of saline solution. /" -——_ ?236 The resting heart rate portions of these studies revealed that most of the tested ketoximes exhibit a negative chronotropic action in rats. Again, the ketoximes of propranol (6a) and timolol (6b) have shown the highest activity in this test, whereas carteolone ketoxime'(6c) and the oxime (6d) were less active. It should be also noted that in this test carteolol (1c) itself has shown the lowest activity on the heart rate of rats. when the potential g-adrenergic antagonist activity of the ketoxime precursors of propranolol, timolol and carteolol was assessed against isoprenaline-tachycardia using the parent compounds as obvious reference drugs as described above, results were in agreement with the findings of the studies on effect on the IOP and resting heart rate. Thus, the ketoxime precursors of propranolol (6a) and timolol (6b) were the most effective whereas (6c) and (6d) were the least active. See Figure i.

These results indicate that at least two of the investigated ketoxime precursors (6a and 6b) have an antiglaucoma activity which is probably linked to their 3-adrenergic antagonistic properties. Yet, whether these properties are due to an inherent intrinsic activity of the ketoximes themselves or are the result of their active biological conversion to their parent drugs needed to be verified. For this reason the in vivo disposition of the ?9novi990 * 223665 r- different ketoximes and their parent 0-blockers in the different ocular tissues was studied in rabbits.

EXAMPLE 7 In vivo distribution - metabolism studies: A. In ocular tissues of rabbits: Adult male New Zealand albino rabbits weighing 2.5-3.5 kg were used. Standard doses of 100 yl of 1% solution of the drugs in saline solution were administered 10 topically to both eyes of each rabbit. After appropriate time intervals ( 30 , 60 and 120 minutes), the animals were sacrificed. Aqueous humor was obtained by making a sinqle puncture at the limbus using a 25 g x 5/8" needle attached to 1 c.c. syringe. Then the cornea and the iris-ciliary 15 body were isolated. The tissues were pooled and homogenized using a Tekmar SDT tissue.mizer in ice cold perchloric acid (0.05 M) which contained 0.05% sodium metabisulfite as antioxidant. Samples were then rehomogenized in CH3OII to prepare 10% homogenates, 20 transferred to micro-filters and centrifuqed for 20 minutes at 10000 r/minute to precipitate proteins. Aqueous humor was analyzed as such without any further dilution.

Aliguots of 5-20 y1 of the 10% tissue homogenate samples were analyzed by HPLC. Quantitation was done by using a ^5 calibration curve obtained by the addition of known amounts of the compound to aqueous humor, iris-ciliary body or cornea obtained from a control rabbit after topical administration of saline solution.

B. In rat's blood: A group of seven adult male Sprague-Dawley rats weighing 150-250 g was used. Animals were intrajugularly injected with propranolone oxime (6a) at a dose of 6 mg/kg. After 1 , 3, 5, 20 , 40 and 60 minutes, one ml of b^ad__was_^ par*tormics nov 1990 ?23665 withdrawn from the jugular vein and dropped immediately into a tared tube containing 1 ml of ice-cold acetonitrile. The tubes were vigorously shaken, centrifuged, decanted and analyzed for propranolol (la) and propranolone oxime (5a) by HPLC. Quantitation was done by using a calibration curve obtained by addition of known amounts of propranolol oxime'HCl (6a) to blood obtained from a control rat pretreated with saline solution.

The results of the ocular tissue tests are set forth in Tables 4 and 5. •91 33 «0 =J 5 o Z z N m O P S § Si ° I 58 / o o o Table 4 Tissue Concentration3 of propranolol (la) and propranolone oxime (5a) at various time intervals following topical administration of propranolone oxime.HCl (6a) [1* .solution) » Concentration of propranolone oxime (5a) Concentration of Propranolol (la) (mcg/g tissue) (mcg/g tissue) Tissue/Time 30 tnin. 60 min. 120 min. 30 min. 60 min. 120 min.

Cornea 23.75+4.91 16,40±5.80 0.00+0.00 1.68i0.75 1.14+0.29 1.14±0.22 N) Iris-Ciliary 7.79+1.10 0.00+0.00 0.00+0.00 2.11+0.29 1.79+0.20 0.43+0.11' Aqueous 0.82+0.09 0.80f0.06 O.OOfO.OO 0.04i0.02 0.7H0.11 - O.OOfO.OO Humor 'Figures represent the mean ± S.E. of the mean of at least 4 rabb.lt's. ro rNJ CM on ON cn 223665 Table 5 Tissue Concentrationa of propranolol at various 11 me 1nterva 1 s following topical administration of proprano 1 o 1 . HC1 (la)(l% solution).

Concentration of propranolol (mcg/g tissue) Tissue/Time 30 min. 6 0 min. 120 min.

Cornea 47.10+5.57 14.54±2.97 0.00+0.00 I r i s-ci1i a ry bo dy 0.05±1.47 O.OOfO.OO 0.00+0.00 Aqueous humor 1 .28 + 0 .19 0 . 26t0.00 0.00 + 0 .00 aF1gures' represent the mean ± S.E. of the mean of four rabbits. ? 2 3 6 6 5 m f- ' 10 . 15 U- The results of the ocular tissue studies show that propranolol (1a) could be detected in measurable concentrations in the different eye compartments for the first two hours following the topical administration of its ketoxime precursor (6a) at its effective ocular hypotensive dose level (1%) (Table 4). On the other hand, propranolol could not be detected in any of the tested eye tissues two hours after its ocular application (Table 5), and it had completely disappeared from the iris-ciliary body which is supposed to be the site of its ocular hypotensive action, one hour after administration. These results might explain the shorter duration of propranolol action on the IOP relative to that of its ketoxime precursor. In addition, these results might also suggest that the ocular hypotensive activity of the oxime is most probably due tor its active conversion to propranolol in situ in the ocular- ' tissues of'rabbits. This is also supported by the finding that following the ophthalmic administration of the other ketoxime precursors (fib and 6c) of timolol and carteolol, respectively, at the low dose level used, the parent (3-adrenerg ic antagonists in any of the eye compartments could not be found. This would suggest that either the ketone formed or the reduced form, the active 0-blocker, is disposed of so fast that it cannot be detected, or that the ketones are not such good substrates for the reductase enzyme as the propanolone ketoxime.

The studies in ocular tissue and blood revealed that the metabolic pathway of the oxime in the blood is quite different from that in ocular tissues. Thus, propranolol was not detected in rat's blood following the i.v. administration of the oxirne and, instead, another more polar compound was detected. However, 5 minutes after injection even this compound had totally disappeared. The oxime itself appeared to have a very fast metabolism in blood (Fig. 2). The t1/2 *n blood was equivalent to 7.64 + 0.55 minutes and one hour after i.v. administration the oxime had / 1 —_ completely disappeared from the blood. 223665 While these results would suggest that the propranolol formed in situ in the iris-ciliary body is responsible for the IOP reduction observed, the ketoxime 5 itself might have intrinsic activity.

Based on the previous observation of the necessity to convert adrenalone to lipophilic esters to be reduced, one could expect that the lipophilic propranolone 50 is easily reduced, while the ketones derived from timolol and carteolol, being less lipophilic (heterocyclic substitution of naphthalene), are not reduced that extensively. The N-isopropyl analog (6d) of timolol was ■ synthesized and tested in order to assess the importance of 35 the N-alkyl function. Propranolol contains an i-propyl group, like 66, but 6d was still found inactive. The difference in the behavior of the 6a vs. 6b-d thus might be due to the difference in the Ar-group which appears to determine the substrate properties necessary to bind to the 5 reductase enzyme. This hypothesis is supported by the relative HPLC retention times of the free bases 5a-5d which were 1 2.86 , 7.22, 3 . 10 , 6.10 for 5a, 5b, 5c and 5d, respectively, indicating that 5a is by far the most lipophilic. 0 The following example illustrates the HPLC analytical method used to obtain these results.

EXAMPLE 8 new Zealand patent office z9nwi990 RECEJVGD ANALYTICAL METHOD A high pressure liquid chromatography (HPLC) method was developed for .the assay of the 0-blockers and their ketoxime analogs in biological fluids. The chromatographic analysis was performed on a system consisting of Beckman Model 112 solvent delivery system, 225665 f1* Model 340 Injector, and Waters Model 481 variable wave length LC spectrophotometer. An ASI reverse phase 15 chroinpack C-jg column, operated at ambient temperature, was used for all separations. The mobile phase used for separation of propranolol (1a) and propranolone oxime (5a) consisted of water, 1-heptane sulfonic acid, 0.1M acetic acid, 0.1M triethanolamine and methanol (90, 1g, 100, 799). 20 With a flow rate of 1.5 ml/minute, the two compounds showed retention times of 2.44 and 3.21 minutes for propranolone oxime and propranolol, respectively. The mobile phase used for separation of carteolol (1c), carteolone oxime (5c), timolol (1b), timolone oxime (5b) and timolone ispropyl 25 oxime (5d) consisted of water, 1-heptane sulfonic acid, 0.1M acetic acid, tetrahydrofuran, 0.1M triethanolamine and methanol (430, 2, 40, 30, 100 and 398). With a flow rate of 1.5 ml/minute, the retention times for these compounds were 3.10, 3.54, 6.10, 7.22 and 9.15 minutes for carteolone 30 oxime (5c), carteolol (1c), timolone isopropyl oxime (5d), timolone oxime (5b) and timolol (lb), respectively.

The results are depicted in Figure 2 which is a plot of blood levels (yg/ml) vs. time of 5a after administration of 6a at a dose level of 6 mg/kg to rats.

It is believed that the compounds of the invention are converted to their parent 0-blockers according to the following scheme A which shows the conversion of 5a to la. Similar conversions would follow scheme B.

The hydrolytically sensitive precursors of the present invention comprise effective chemical delivery systems (CDS) for the b-blockers and intraocular pressure reducing agents.

WEW2EAU/VD ^ patent office NOV 1990 Received scheme a hoh' 0-ch2-c-ch2nhch(ch3) HYDROLYSIS >■ oh 5a 0-CH2-C-CH2NHCH(CH3) reductase v h2-ch-ch2nhch(ch3)2 lo a scheme b n-oh Ar-x- ch2-c-ch2-nhr h?0 0 II ■f Ar-x-CH2- c-ch^-nhr OH I ->• Ar-X-CH2-C-CH2-NHR I H ro ro Ovl On cn ui 223665 The compounds of the invention may be administered to animals in need thereof by instilling solutions thereof into the eye or via oral tablets, capsules, etc., or any other convenient route of administration at dosages of from about 0.001 to about 20 mg/kg.

The compounds may be formulated with any conventional pharmaceutically acceptable carrier, such as those utilized for the parent amino-alcohol B-blockers.

Claims (1)

1. WHAT WE CLAIM IS: 223 GB 5 1. A compound having the formula 5 Y II Ar-X-CH2-C-CH2-NHR (I) or a pharmaceutically acceptable acid addition salt 10 thereof, wherein -X- is -0-, -CH2- or -; =Y is a derivatized keto group which is hydrolyzable or enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 20 carbon atoms, the aralkyl group optionally bearing methoxy 15 substituents on the aryl portion thereof; and Ar is the 3-aromatic or heterocyclic residue of a l-alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having (B-adrenergic blocking properties. 20 25 2. A compound or salt according to Claim 1, wherein =Y is =N-OR1, =N-NH2, =N-NR1R2, ■ ^S—! O—1 *3 ' or \ ~R3 , NH—1 » Rq_ and R2 may be the same or different and are H or alkyl having from 1 to 8 carbon atoms; and R3 is R^, -COOR-^ or -CON(Ri)2 wherein R^ is defined as above. W 3 0 3. A compound or salt according to Claim 2, wherein =Y is =N0Ri wherein R^ is H or alkyl having from 1 to 8 carbon atoms. 4. A compound or salt according to Claim 3, wherein 35 =Y is =NOH. 5. A compound or salt according to any one of the preceding claims, wherein -X- is -0-. 37 2 2 8 G a 5 6-. A compound or salt according to any one of Claims 1-5, wherein R is isopropyl. 7. A compound or salt according to any one of Claims 1-5, wherein R is t-butyl. 8. A compound or salt according to any one of Claims 1-5, wherein R is benzyl. 9. A compound or salt according to any one of Claims 1-8, wherein Ar is 10. A compound or salt according to any one of Claims 1-8, wherein Ar is 11. A compound or salt according to any one of Claims 1-8, wherein Ar is S' - 38 - 12. A compound or salt according to any one of Claims 1-8, wherein Ar is O o '">£■> .'■> r* 10 15 ch2ch2-o-ch3 20 14. A compound or salt according to any one of Claims 1-8, wherein Ar is 2 5 15. A compound or salt according to any one of Claims 1-8, wherein Ar is 30 %o - 39 - 1<5. A compound or salt according to any one of Claims 1-8, wherein Ar is 2 2 m* 5 & CN C 10 15 17. The compound of Claim 1 having the formula N-OH il 0-CH2-C-CH2-NH-CH(CH3)2 or a pharmaceutically acceptable acid addition salt thereof. 20 25 30 18. The compound of Claim 1 having the formula 0 N-OH 0-CH2-C-CH2-NH-C(CH3)3 vn or a pharmaceutically acceptable acid addition salt thereof. 19. The compound of Claim 1 having the formula 35 fot N-OH II 0-ch2-c-ch2-nh-ch(ch3J2 2-CH=CH 2 - 40 - or a pharmaceutically acceptable acid addition salt thereof. 20. The compound of Claim 1 having the formula 223 G (if 10 n-oh II 0-ch2-c-ch2-nh-ch(ch3)2 ch,-ch2-o-ch2 < or a pharmaceutically acceptable acid addition salt 15 thereof. 21. The compound of Claim 1 having the formula 20 N-oh 0-ch2-c -ch2-nh-ch2ch2 .-ch3 —\oy~o-ch-. 25 CH or a pharmaceutically acceptable acid addition salt thereof. 30 35 22. The compound of Claim 1 having the formula N-OH II 0-ch 2-c -ch 2-nh-c (ch j) 3 ir asmr' -- M S$5S«H\v - 4i - 228GG5 or a pharmaceutically acceptable acid addition salt thereof. 23. The compound of Claim 1 having the formula N-oh II 0-ch2-c -ch2-nh-ch(ch3)2 10 CH2CH2-0-CH3 or a pharmaceutically acceptable acid addition salt 15 thereof. 24. The compound of Claim 1 having the formula 20 N-OH (I 0-chz-c-ch2-nh-ch(ch3)2 0chz-ch=ch2 O 25 or a pharmaceutically acceptable acid addition salt thereof. 30 35 25. The compound of Claim 1 having the formula n-oh il 0-ch -c-ch2-nh-c(ch3)3 |Vp"/ . 42 . 22 or a pharmaceutically acceptable acid addition salt thereof. 26. The compound of Claim 1 having the formula n-oh If 0-ch2-c-ch2-nh-ch(ch3)2 10 or a pharmaceutically acceptable acid addition salt thereof. 15 27. The compound of Claim 1 having the formula N-oh II 0-CH2-C-CH2-NH-CfCH3)3 20 i cl ^ CH3 or a pharmaceutically acceptable acid addition salt thereof. 25 28. A method for eliciting a p-adrenergic blocking response in a non-human warm-blooded animal in need thereof, which comprises administering to said animal an effective p-adrenergic blocking amount of a compound having the formula 30 Y II Ar-X-CH2-C-CH2-NHR (I) or a pharmaceutically acceptable acid addition salt 35 thereof, wherein -X- is -O-, -CH2- or -; =Y is a derivatized keto group which is hydrolyzable or ' • 228 - 43 - enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 20 carbon atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar 5 is the 3-aromatic or heterocyclic residue of a 1- alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having p-adrenergic blocking properties. 10 29. A method according to Claim 28, wherein =Y is =N0H. 30. A method according to Claim 28 or 29, wherein -X- is -0-. 15 20 31. A method according to any one of Claims 28-3 0, wherein Ar is selected from the group consisting of W 25 30 ch2-ch2-o-ch2 -<] , o-ch2ch=ch2 2 and :*SSSR?lt-£r: r- 22'miu15 10 15 - 44 - 32. A method according to Claim 28, wherein the compound administered is selected from the group consisting of N-OH II 0-CH2-C-CH2-NH-CH(CH3)2 N-OH If 0-CH,-C -CH2-NH-C(CH3) // \ V/N ■ 3*3 , 20 N-OH 0-CH2-C -CH 2-NH-CH (CH3 J 2 ©r \^^CH2-CH=CH2 N-OH II O-CH 7-C -CH 2-N H-CH (CH 3 J 2 ch2-ch2-o-ch2 -<J 25 30 3 35 N-OH 0-CH2-C -CH2-*H-C (CH ) CN N-OH I! O-CH j-C -CH 2-*H-CH (CH 3) 2 /• ch2ch2-o-ch3 jz 3°jani99r^l // - 45 - ^ •«. o 10 15 20 25 30 35 N-OH O-CH 2-C -CH 2-NH-CH (CH 3) 2 och2-ch=ch2 223GG5 N-OH II 0-CH2-C -CH2-NH-C(CH3)3 N-OH 0-CH2-C-CH2-NH-CH{CH3J2 CI and N-OH II 0-CH2-C -CHp-NH—CfCH J ^ z 3 3 CH- o and the pharmaceutically acceptable acid addition salts thereof. 33. A pharmaceutical composition of matter, in unit dosage form, for use in eliciting a p-adrenergic blocking response in a warm-blooded animal, said composition comprising an effective p-adrenergic blocking amount of a compound having the formula Y II Ar-X-CH2-C-CH2-NHR (I) or a pharmaceutically acceptable acid addition salt thereof, wherein -X- is -0-, -CH2- or -; =Y is a derivatized keto group which is hydrolyzable or enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 20 carbon atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar is the 3-aromatic or heterocyclic residue of a l-alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having p-adrenergic blocking properties; and a non-toxic pharmaceutically acceptable carrier therefor. - 46 - 22o(;t>5 34. A composition according to Claim 33, wherein =Y is =NOH. 5 35. A composition according to Claim 33 or 34, wherein -X- is -0-. 36. A composition according to any one of Claims 33-35, wherein Ar is selected from the group consisting of 10 15 /~\ v 20 25 ch2ch2-och3 CH2CHaCH2 ^w/ 30 o-ch2ch=ch2 and cn - 47 - 223BG5 37. A composition according to Claim 33, comprising an effective (3-adrenergic blocking amount of a compound having the formula n-oh II o-ch 2-c -ch ,-nh-ch (ch3) 2 n-oh 0-ch2-c-ch2-nh-c(ch3) 3 // w V" n-oh © )-ch ,-c -ch -nh-ch (ch 3) 2 ch7-ch=ch2 N-OH II o-chj-c -ch2-«h-ch(ch3]2 /V n t ll \\ 5°janl99r>jl V - 48 - N-OH O-CH 2-C-CH 2-NH-C (CH 3) 3 (°t 223 (JM II O-CH j-C -CH 2-«H-CH(CH 2 ch2ch2-o-ch3 N-OH II 0-CH2-C -CH2-NH-CH(CH3)2 och2-ch=ch2 N-OH II O-CH 2-C -CH 2-N H-C (CH 3 J 3 N-OH 0-CH2-C-CH2-NH"CHfCH3J2 or 'ch- C! n-OH II O-CH^-C -CH2-NH-CfCH3)3 CH3 or a pharmaceutically acceptable acid addition salt thereof. 38. A method for the treatment of glaucoma or for lowering intraocular pressure in a non-human warmblooded animal in need thereof, which comprises administering to the eye or the eyes of said animal an effective intraocular pressure reducing amount of a compound having the formula Y II Ar-X-CH2-C-CH2-NHR (I) or a pharmaceutically acceptable acid addition salt thereof, wherein -X- is -0-, -CH2- or -; =Y is =0 or a tBSISRB?? C C 10 ~49" 22;.;tit;5 derivatized keto group which is hydrolyzable or enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 2 0 carbon atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar is the 3-aromatic or heterocyclic residue of a l-alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having p-adrenergic blocking properties. 39. A method according to Claim 38, wherein =Y is =N-OR1, =N-NH2, =N-NR1R2,^'0I]-R3,^SIl_R3f or^S"Z|_R o—J 0— NH—1 15 Ri and R2 may be the same or different and are H or alkyl having from 1 to 8 carbon atoms; and R3 is Rj_, -COOR^ or -CON(Ri)2 wherein is defined as above. 40. A method according to Claim 39, wherein =Y is 20 =N0Ri wherein R^ is H or alkyl having from 1 to 8 carbon atoms. 41. A method according to Claim 40, wherein =Y is =N0H. 25 42. A method according to any one of Claims 38-41, wherein -X- is -0-. - • - * — Jas0»E&?' - 50 - 32 o GC5 43. A method according to any one of Claims 38-42, wherein Ar is selected from the group consisting of ■ Qt% ■ 10 15 20 25 ch2ch2-o-ch3 o-ch2 ch=ch2 2 and H 30 35 44. A method according to Claim 38, wherein the compound administered is selected from the group consisting of N-OH II O-CH 2-C -CH 2-NH-CH (CH 3) 2 55- - 51 - n-oh II o-ch2-c -ch2-nh-c {ch3 )3 223GG5 // \\ \/N n-oh ch2-ch=ch2 n-oh II o-ch ,-c -ch ,-n h-c h f ch, j ,22 1 3 2 W n-oh II 0-ch2-c-ch2-*H-c(ch3)3 cn n-oh II o-chj-c -ch2-nh-ch(ch3j n-oh II o-chj-c -ch2-hh-ch(ch3j2 & 0ch2-chsch2 n-oh II 0-ch2-c-ch2-nh-c(ch3)3 - 52 - o o •» pi'r (icobb 0 N-OH 0-CH2-C-CH2-NM~CH(CH3)2 N-OH II 0-CH2-C -CH2-nh-C(CH3J J and and the pharmaceutically acceptable acid addition salts thereof. Vhcs 'j 10 45. An ophthalmic pharmaceutical composition of matter, in unit dosage form, for use in the treatment of glaucoma or in the lowering of intraocular pressure in a warm-blooded animal, said composition comprising an effective intraocular pressure reducing amount of a 15 compound having the formula Y II Ar-X-CH2-C-CH2-NHR (I) 2 0 or a pharmaceutically acceptable acid addition salt thereof, wherein -X- is -0-, -CH2, or -; =Y is =0 or a derivatized keto group which is hydrolyzable or enzymatically convertible to a keto group; R is alkyl having 1 to 12 carbon atoms or aralkyl having from 7 to 2 0 2 5 carbon atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar is the 3-aromatic or heterocyclic residue of a 1-alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having 3 0 p-adrenergic blocking properties; and a non-toxic ophthalmically acceptable carrier therefor. 46. A composition according to Claim 45, wherein 35 =Y is =N-0R]_, =N-NH2, =N—NR^_R2 , —R3 , —j—R3 , or^ —I—R3 ; 0—1 O—1 NH—1 - 53 - O O '1 i ■>,' * c~ /c o b b 0 and R2 may be the same or different and are H or alkyl having from 1 to 8 carbon atoms; and R3 is Rlf -COOR! or -CON(R1)2 wherein is defined as above. 5 47. A composition according to Claim 46, wherein =Y is =NOR^ wherein is H or alkyl having from 1 to 8 carbon atoms. 10 48. A composition according to Claim 47, wherein =Y is =N0H. 49. A composition according to any one of Claims 45-48, wherein -X- is -0-. 15 50. A composition according to any one of Claims 45-49, wherein Ar is selected from the group consisting of 20 w o C O 25 30 ch2ch=ch2 35 ch2ch2-o-ch3 isessgg®^*-''. "'r - 54 - 22 0-CH2CH=CHj and CN o 10 15 20 51. A composition according to Claim 45, comprising an effective intraocular pressure reducing amount of a compound having the formula N-OH II O-CH 2-C -CH 2-NH-CH(CH j) 2 N-OH II 0-CH2-C-CH2-NH-C(CH,) 2'3 /* \ \./» 25 N-OH II 0-CH2-C-CH2-NH-CH(CH3)2 ch2-ch=ch2 N-OH If 0-CH2-C -CH2-NH-CH(CH3J2 CHj-CHj—O-CHj 30 35 yO-CH, N-OH O-CHj-C-CHj-NH^HjCHj -/qV-O-CH. CH. <1 - 55 - n-oh O-CH 2"C -CH 2-*H-C (CH 3) 3 223 Gb'5 n-oh II O-CHj-C -CH 2-NH-CH f CH ,) 3 2 CH2CH2-0-CH3 o 10 15 n-oh 20 OCH 2-C -CH j-NH-CH (CH 3) 2 och2-ch=ch2 N-OH O-CH 2-C -CH 2-NH-CH (CH 3J 2 or CI N-OH II 0-CH2-C -CH2-NH-C(CH3)3 N-OH II O-CH 2-C-CH 2-NH-C (CH 3) 3 ch. O or a pharmaceutically acceptable acid addition salt thereof. G 25 52. A method for producing in the ocular tissue of a non-human warm-blooded animal an effective intraocular pressure lowering amount of a p-adrenergic blocker of the formula OH 30 | Ar-X-CH2-CH~CH2-NHR (II) wherein -X- is -O-, -CH2- or -? R is alkyl having from 1 to 12 carbon atoms or aralkyl having from 7 to 20 carbon 35 atoms, the aralkyl group optionally bearing methoxy substituents on the aryl portion thereof; and Ar is the 3- s Vj. a V 223(565 - 56 - aromatic or heterocyclic residue of a l-alkylamino-2-propanol having an optionally substituted aromatic or heterocyclic substituent at the 3-position and having p-adrenergic blocking properties; said method comprising administering to the eye- or eyes of said animal a quantity of a precursor of said p-adrenergic blocker of formula (II) which is bioconvertible in ocular tissue into said p-adrenergic blocker of formula (II) via the corresponding ketone intermediate of the formula 0 II Ar-X-CH2-C-CH2NHR (IV) wherein Ar, X and R are defined as above, said quantity of said precursor being sufficient to result via the intermediate ketone in ultimate release of an effective intraocular pressure lowering amount of said p-adrenergic blocker of formula (II) in the ocular tissue of said animal. 53. A method according to Claim 52, wherein the p-adrenergic blocker of formula (II) is selected from the group consisting of propranolol, timolol, carteolol, befunolol, metipranolol, betaxolol, celiprolol, alprienolol, metoprolol, penbutolol, oxprenolol, bunitrolol, pindolol, atenolol, falintolol, moprolol, nadolol, bufuralol, labetolol, bevantolol, bupranolol, cetamolol, levobunolol, mepindolol and toliprolol. 54. A compound having the formula defined in Claim 1 substantially as herein described with reference to the Examples and/or the accompanying drawings. 52386 57 55. A pharmaceutical composition in unit dosage form according to Claim 33 or Claim 45 substantially as herein described with reference to the Examples and/or the accompanying drawings. 56. A method as claimed in Claim 28, Claim 38 or Claim 52, substantially as herein described with reference to the Examples and/or the accompanying drawings. .V.'/Yv.V, Sr/Sr. i.l .7. .9/7. ^: 'rSfiV. J? ^ By fcUs/Their authorised Agent A.J. PARK & SON Per: